This invention discloses precursors that can be used effectively for the synthesis of 19-nor-vitamin D analogues, as well as a method and intermediates for the preparation thereof. More specifically, the invention relates to precursors of the A-ring of said vitamin D analogues, which A-ring is represented by the structure below ##STR2##
(see for instance Mazur et al., Tetrahedron Letters 1995, 2987).
The synthesis of bicyclo[3.1.0]hexane derivatives, as 19-nor- A-ring precursors has been developed from (-)-quinic acid or cyclohexane-triol by M. Vandewalle et al. (Tetrahedron Letters, 1995, 36 (45), 8299-8302) and is based on the well-known sigmatropic rearrangement of cyclopropylic alcohol into homoallylic alcohol. The potential of this rearrangement in natural vitamin D has been first demonstrated by Mazur et al. (op. cit.). An alternative synthesis from 2,4-pentane-dione was also reported (S. Z. Zhou, S. Anne, M. Vandewalle, Tetrahedron Letters, 1996, 37 (42), 7637-7640). 3-Cyclopentenol was also used as a precursor for this preparation (W. Yong, M. Vandewalle; Synlett, 1996, 9, 911-912).
These methods however present the following disadvantages:
The preparation from (-)-quinic acid involves a radicalar desoxygenation which is difficult to control on large quantity, and the use of toxic tributltinhydride; PA1 The process from cyclohexane triol is conducted via a large number of steps (12) and needs two enzymatic reactions; PA1 The starting material, 3-cyclopentenol is not commercially available. It must be prepared from cyclopentadiene via a low yielding (30%) hydroboration step. Furthermore the cyclopropanation and the introduction of the formyl group are cumbersome; PA1 The synthesis starting from 2,4-pentane dione (10 steps) suffers from low yields in the first step for preparing the intermediate bis epoxide. Furthermore, due to their low molecular weight some intermediates are rather volatile and difficult to purify in a large scale process. PA1 A is a group --CH.sub.2 OH, --CH.sub.2 --OCOR', --COR", --CSR" or an ethynyl; PA1 R is hydrogen or a (C.sub.1 -C.sub.6)alkyl; PA1 R.sub.1 is hydrogen, a (C.sub.1 -C.sub.6)alkyl or a group --(CH.sub.2).sub.n --OP; PA1 R.sub.2 is hydrogen or a group --OP; PA1 R' is a (C.sub.1 -C.sub.6)alkyl or a phenyl; PA1 R" is hydrogen, a hydroxyl, a (C.sub.1 -C.sub.6)alkyl, a (C.sub.1 -C.sub.6)alkoxy, a (C.sub.1 --C.sub.6)alkylthio, or a di(C.sub.1 -C.sub.3)alkylamino; PA1 P is hydrogen; a (C.sub.1 -C.sub.6)alkanoyl; a benzoyl in which the phenyl is optionally substituted by a (C.sub.1 -C.sub.4)alkyl, a halogen or a nitro; a (C.sub.1 -C.sub.6)alkoxycarbonyl; a group --Si(R.sub.3).sub.3 in which each R.sub.3 independently represents a (C.sub.1 -C.sub.6)alkyl or a phenyl; a mono- or di-(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl; a tetrahydrofuranyl; or a tetrahydropyranyl; PA1 n is 0, 1, 2, 3 or 4, preferably 0 or 1, PA1 (i) reacting a compound of formula 1 ##STR4## PA1 in which A is a (C.sub.1 -C.sub.6)alkoxycarbonyl, preferably a methoxycarbonyl, or a di(C.sub.1 -C.sub.3)alkylaminocarbonyl and R is as defined above, with a lipase in a vinylalkanoate or an acid anhydride, and PA1 (ii) converting the resulting compound of formula 2 or 2' ##STR5## PA1 in which Z is an alkyl such as a (C.sub.1 -C.sub.6)alkyl, preferably a (C.sub.1 -C.sub.3)alkyl to the corresponding compound of formula (I). PA1 A is a group --CH.sub.2 OH, --CH.sub.2 OCOR', --COR" or an ethynyl; PA1 R.sub.1 is a (C.sub.1 -C.sub.6)alkyl or a group --(CH.sub.2).sub.n --OP; PA1 R' is a phenyl; PA1 R" is hydrogen; PA1 P is hydrogen or a group --Si(R.sub.3).sub.3 ; PA1 n is 0 or 1. PA1 in which: PA1 in which: PA1 in which A is as defined above and R is a (C.sub.1 -C.sub.6)alkyl.